Received for publication July 26, 2006.
Revised October 12, 2006.
Accepted for publication November 6, 2006.

Hydroxyamide analogues of propofol exhibit state-dependent block of sodium channels in hippocampal neurons: implications for anticonvulsant activity

Abstract

Although propofol is most commonly known for its general anesthetic properties, at sub-anesthetic doses propofol has been effectively used to suppress seizures during refractory status epilepticus (RSE), a mechanism, in part, attributed to the inhibition of neuronal sodium (Na) channels. In this study, we have designed and synthesized two novel analogues of propofol, HS245 and HS357, and determined their effects on Na currents recorded from cultured hippocampal neurons. HS357 had greater affinity for the inactivated state of the Na channel than propofol and HS245 (0.22 versus 0.74 and 1.2 µM, respectively) and exhibited the greatest ratio of affinity for the resting over the inactivated state. HS357 also demonstrated greater use-dependent block and delayed recovery from inactivation in comparison to propofol and HS245. Under current clamp conditions, action potentials from hippocampal CA1 neurons in slices were evoked by current injection, or following perfusion with a zero Mg²⁺/7 mM K⁺ artificial cerebrospinal fluid solution. Propofol and HS357 reduced the number of current-induced action potentials; however, HS357 caused a greater reduction in the number of spontaneous action potentials. Consistent with these electrophysiology studies, propofol and HS357 protected mice against acute seizures in the 6 Hz (22 mA) partial psychomotor model. Efficacious doses of propofol were associated with an impairment of motor coordination as assessed in the rotorod toxicity assay. In contrast, HS357 demonstrated a two-fold greater protective index than propofol. Thus, propofol analogues represent an important structural class from which not only effective, but also safer anticonvulsants may be developed.

Key words: anticonvulsants, epilepsy, hippocampal neurons, patch clamp, propofol, sodium channels